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The Cell Fate Decision: A Pathway Responding to Genotoxic Stress
Important Terms * Ataxia Telangiectasia Mutated (ATM)- A protein kinase * Nuclear factor-kappa B (NF-kappa B)- A pro-survival transcription factor. * NF-kappa B essential modulator (NEMO)- A regulatory protein complex. * I Kappa B Kinase (IKK)- Activator of NF-Kappa B To be, or not to be All living organisms, in order to adequately survive, must cope with genotoxic stress. Genotoxic stress is considered to be insults that threaten the integrity and proper function of genes. In order to deal with genotoxic stress cells use "cell-cycle checkpoints", DNA repair mechanisms, eliminate damaged DNA, or programmed cell death. Until recently the mechanisms behind this cellular fate decision have remained elusive. In a 2006 paper published in Science by Wu et. al. the mechanisms behind the cellular response to the most dangerous genotoxic stress was detailed. The paper covered the human cell's response to a DNA double strand break. What has been known about the cellular response to the DNA double strand break is that the protein kinase ATM is activated, and phosphorylates many proteins involved in cell-cycle control, DNA repair, or cell death. However, Wu et. al. have identified a new substrate for ATM called NEMO. NEMO's role in the cell is to modulate the pro-survival transcription factor NF-kappa B. NF-kappa B and its activator IKK are normally found in its dormant state in the cytoplasm waiting to respond to external cellular signals. However, the ATM-NEMO pathway works in the opposite direction. That means that the signal cascade begins in the nucleus and activates the IKK-NF-kappa B system in the cytoplasm. Another unique quality of the ATM-NEMO mechanism is that it is signal specific, responding only to double strand breaks and not to other sources of environmental stress. There are many well known targets of the protein kinase ATM, but NEMO is one of the first cell-death antagonizing target. It is believed that ATM activates so many cell death promoting targets and only a few cell-death antagonizing targets in order to provide a larger window of time for the DNA damage to be repaired and allow the cell to return to a healthy state. The Figure * ATM responds to the signal of a DNA double strand break. * In the nucleus NEMO is associated with a peptide, SUMO. SUMO prevents NEMO from leaving the nucleus, and earmarks it for phosphorylation by ATM. * Once NEMO is phosphorylated by ATM, SUMO leaves and ubiquitin binds. The NEMO-ATM-Ubiquitin complex can now leave the nucleus. * In the cytoplasm NEMO and its associated peptides phosphorylate the IKK complex. IKK activation requires the presence of ELKS protein and active ATM kinase. * Active IKK can now activate NF-Kappa B which enters the nucleus and stimulates expression of pro-survival genes. The Downside The downside of this pathway is that evidence of NF-kappa B constitutively expressing pro-survival genes has been found in diverse types of cancer. References Bartek, J. "CELL BIOLOGY: The Stress of Finding NEMO." Science 311.5764 (2006): 1110-111. Web. 3 Dec. 2014. "Genotoxicity." Wikipedia. Wikimedia Foundation, 30 Nov. 2014. Web. 03 Dec. 2014. . Kauppinen, Tiina M., Li Gan, and Raymond A. Swanson. "Download PDFs."Poly(ADP-ribose) Polymerase-1-induced NAD+ Depletion Promotes Nuclear Factor-κB Transcriptional Activity by Preventing P65 De-acetylation. Elsevier, 15 Apr. 2013. Web. 03 Dec. 2014. .